Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence
Mitochondria are crucial organelles in the production of energy and in the control of signaling cascades. A machinery of pro-fusion and -fission proteins regulates their morphology and subcellular localization. Both mechanisms are evolutionarily conserved from yeast to humans. In mammals, mitofusin (MFN) 1 and 2 and optic atrophy protein 1 (OPA1) are required for fusion of the outer mitochondrial membrane and inner mitochondrial membrane (Romanello and Sandri, 2016). OPA1 requires MFN1 to regulate mitochondrial fusion, but on the other hand, oligomerization of OPA1 regulates apoptosis by controlling cristae remodeling and cytochrome c redistribution (Cipolat et al., 2006, Frezza et al., 2006). The maintenance of a dynamic mitochondrial network is particularly important for cells with a complex and highly structured cytosol, such as neurons and cardiac and skeletal muscles constituted by post-mitotic cells that do not divide. While tissues with high cell turnover can dilute the damaged/altered mitochondria among the dividing cells, the post-mitotic tissues use the fusion/fission machinery to preserve or restore mitochondrial function. Alternatively, post-mitotic organs activate selective autophagy to remove the irreversibly injured mitochondria (mitophagy). A failure of these systems predisposes to tissue dysfunction and degeneration. Mouse knockouts (KO) for each of the pro-fusion genes (Mfn1, Mfn2, and Opa1) are lethal to embryos because of mitochondrial dysfunction (Chen et al., 2003, Davies et al., 2007). Muscle-specific KO mice for Mfn1 and Mfn2 are viable at birth, although they display profound defects of muscle growth characterized by mitochondrial dysfunction, reduction of mitochondrial DNA (mtDNA) in skeletal muscle, and accumulation of point mutations and deletions in the mitochondrial genome that cause death within 6–8 weeks of age (Chen et al., 2010). In humans, mutations in MFN2 and OPA1 genes cause two neurodegenerative diseases, Charcot-Marie-Tooth type 2A (CMT2A) and dominant optic atrophy (DOA), respectively (Alexander et al., 2000, Delettre et al., 2000, Züchner et al., 2004). CMT2A is an inherited neuropathy that is clinically characterized by muscle atrophy. Heterozygous missense recessive mutations of OPA1 genes cause DOA with a muscle involvement revealed as an aspecific myopathy with mitochondrial features (Amati-Bonneau et al., 2008, Schaaf et al., 2011). Interestingly, the first case of homozygous missense mutation has been reported in two sisters that died at 2 and 10 months of age showing myopathy, encephalopathy, and cardiomyopathy (Spiegel et al., 2016). The muscle biopsies of these sisters revealed 50% reduction of OPA1 protein, a decrease in the activity of all the respiratory chain complexes, and an important mtDNA depletion (80%). Therefore, mutations in fusion genes result in brain and muscle dysfunction.
Skeletal muscle is a major site of metabolic activity and the most abundant tissue in the human body, accounting for almost 50% of the total mass. Being the largest protein reservoir, muscle serves as a source of amino acids to be utilized for energy production by various organs during catabolic periods. Importantly, skeletal muscle is an important modulator of general metabolism since it plays an important role in glucose, amino acid, and lipid homeostasis. Recent data in Drosophila show that maintenance of a functional proteostasis specifically in muscles, but not in white adipose tissue, during aging reverberates to the whole organism, leading to an extension of lifespan (Demontis et al., 2014, Demontis and Perrimon, 2010). Therefore, a new concept is emerging from this and other studies that considers the metabolic adaptations occurring in skeletal muscles as disease modifier/controller (Baskin et al., 2015). Indeed, growing evidence suggests that muscle-derived growth factor or cytokines, known as myokines, modulate systemic physiology (Demontis et al., 2013). Importantly, exercise by preserving and ameliorating muscle metabolism is able to counteract the body deterioration by improving function of multiple organs (Neufer et al., 2015). However, the mechanistic insights that link muscle contraction to organ function and longevity are still unknown. Here we show that deletion of Opa1 in skeletal muscle results in a lethal phenotype that is even more severe than Mfn1/2 double KO. This phenotype results from suppression of myogenesis, impaired protein synthesis and activation of protein breakdown. Importantly, several of these features were recapitulated in inducible muscle-specific Opa1 KO mice that additionally show multiple-organ senescence and precocious aging.
Aging has been reported to be accompanied by numerous functional alterations of mitochondria, including changes of mitochondrial dynamics (Ibebunjo et al., 2013). Thus, we tested whether mitochondria-shaping factors are reduced in humans. A decline of Mfn1/2, Opa1, and Drp1 transcripts was found in muscle biopsies of old sedentary (sarcopenic) subjects (Figure 1A and Table S1). Since exercise counteracts most of the age-related features, including the decline in muscle mass/force, we tested whether a long-life regular exercise was able to prevent the reduction of these genes (Figure 1A). Expression of the mitochondria-shaping genes was maintained in muscle biopsies of senior sportsmen. Similar to transcript level, we further confirmed that OPA1, MFN1, and DRP1 proteins were reduced in sedentary subjects and that regular exercise was able to counteract this decline (Figures 1B, S1A, and S1B). When we explored whether the decrease of mitochondrial shaping proteins correlates with muscle mass loss in elderly people, we found a significant correlation only for OPA1 and not for DRP1 or MFN1 (Figure 1C). Similarly, muscle force drop significantly correlates with decrease of OPA1 expression but not of DRP1 or MFN1 (Figure 1D). This association is independent of fiber type (Figures S1C and S1D). Consistently with human data, aged mice displayed a significant reduction of OPA1 in muscles (Figures 1E and S1E). Importantly, 1 week of exercise training is sufficient to reactivate OPA1 expression in muscles of aged mice (Figure 1E). Overall, these findings suggest a causative role of mitochondrial dynamic impairment that correlated with the decreased OPA1 expression and age-related muscle loss and weakness.
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